Project 3 will test the overarching hypothesis that variation in the gene (ADRA2A) encoding the a2A- adrenergic receptor (a2A-AR) is an important determinant of platelet aggregation and insulin secretion in pathological and physiological conditions that occur in the setting of sympathetic activation. Recent independent lines of evidence, including our own studies, implicate a2A-AR genetic variation, particularly haplotype 4 (characterized by rs553668, a variant present in 16-24% of people), as a mediator of important differences in adrenergically-mediated responses. However, the clinical consequences of such variability, which are most likely to be manifest under conditions of sympathetic activation, are not known. Platelet aggregation in response to epinephrine is mediated by a2A-ARs; there is increased aggregation and increased risk of myocardial infarction concurrent with the early morning diurnal peak in sympathetic activity. The contribution of genetic variability to adrenergically-mediated diurnal platelet responses is not known. Accordingly, Specific Aim 1 will test the hypothesis that ADRA2A haplotype affects diurnal platelet aggregation responses. Sympathetic activation, in addition to increasing platelet aggregation, also inhibits insulin secretion; this response is mediated by a2A-ARs and is affected by ADRA2A genetic variation, in particular, haplotype 4. Two conditions characterized by hyperglycemia in the setting of sympathetic activation are stress-induced hyperglycemia, such as commonly occurs in patients with serious illness, and gestational diabetes. Thus, we will test the hypothesis that ADRA2A haplotype is associated with increased risk of stress-induced hyperglycemia in patients with myocardial infarction (Specific Aim 2), and gestational diabetes (Specific Aim 3). The proposed studies will translate basic science findings and previous genetic discovery studies into fundamental mechanistic information that is clinically relevant. This will allow, on the basis of genetic information, the future targeting for interventions those individuals at increased risk of specific adverse outcomes that occur under conditions characterized by increased sympathetic drive. RELEVANCE (See instructions): Sympathetic activation is important in the pathogenesis of many diseases. The ability to identify patients at high risk of complications mediated by increased sympathetic activity would allow the eariy identification of disease and targeted interventions to prevent complications in this group.